1. No category

Vol. 3 (1), pp. 117-125, April, 2015.
© Global Science Research Journals
http://www.globalscienceresearchjournals.org/
Global Journal of Microbiology Research
Review
Prevalence of multidrug-resistant tuberculosis and
convergence of MDR-TB and HIV infection
Gosa Girma
Department of Biology, Stream of Natural Science, Asella College, Asella, Ethiopia
E-mail: [email protected]
Accepted 2 April, 2015
Abstract
The rationale of this review is to describe the current status of Multi-drug resistant tuberculosis (MDRTB) and the epidemic of MDR-TB and HIV co-infection through a systematic review of the literature in
worldwide. TB is an infectious disease caused by the bacterium Mycobacterium tuberculosis that
transmitted through aerosol droplets and one of the world’s most devastating human pathogens that
cause more than 2 million deaths annually. On the other hand, Multidrug-resistant tuberculosis (MDRTB) caused by M. tuberculosis strains resistant to at least isoniazid (INH) and rifampin (RMP) has
emerged as a significant global epidemic resulting largely from deficiencies in TB case management
and program management. Subsequently, there are alarming reports of increasing drug resistance from
various parts of the globe. Moreover, the most important risk factor for the development of MDR-TB is
previous anti-tuberculosis therapy. Studies indicated that approximately 425,000 MDR-TB cases occur
annually worldwide, representing nearly 5% of the world’s annual TB burden. On the other hand, the
human immunodeficiency virus (HIV) is a driving force behind the global burden of TB and the
development of drug-resistant TB. Obviously, the growing HIV infection epidemic presents massive
challenges to TB control programs at all levels and could fuel further increases in anti-TB drug
resistance and hence people living with HIV have a higher risk of MDR. The synergy between TB and
HIV is strong; in high HIV prevalence population, TB is a leading cause of morbidity and mortality.
Therefore, managing the treatment of existing cases properly is the key in prevention of the spread of
MDR-TB through taking all of the medications exactly as prescribed by the healthcare providers.
Keywords: HIV; MDR-TB; M. tuberculosis; Prevalence; Risk factor
BACKGROUND
Tuberculosis (TB) is an infectious bacterial disease
caused by Mycobacterium tuberculosis that most
commonly affects the lungs and remains one of the
world’s deadliest communicable diseases (Raviglione et
al., 2012; Zhao et al., 2012; WHO, 2014a). It continues to
be a major public health problem in the worldwide and
one-third of the world population was infected by
Mycobacterium (Sohail, 2006; Dara et al., 2009).
Moreover, it ranks as the second leading cause of death
worldwide from a single infectious agent, after the human
immunodeficiency virus (WHO, 2013). It is spread by
people with active respiratory disease through the air.
People who have TB disease in their lungs can release
tiny particles containing Mycobacterium tuberculosis into
the air by coughing, sneezing or even talking (WHO,
2012 and TB Alliance, 2012b). TB usually affects the
lungs, but it can also affect other parts of the body, such
as the brain, the kidneys or the spine.
Still, TB is a leading cause of death by an infectious
disease worldwide, despite global efforts and financial
investment by governments and non-govern mental
organizations in disease control programmes during the
past 20 years (Raviglione et al., 2012). In most cases,
although TB is treatable and curable, persons with TB
can die if they do not get proper treatment (CDC, 2012).
According to the report of WHO, in 2013, about 9.0
Glob. J. Microbiol. Res. 118
million people developed TB and 1.5 million died from the
disease, of these 360 000 were HIV-positive (WHO,
2014a).
As global status of Tuberculosis indicated, TB remains
a major global public health concern (Zhao et al., 2012).
Worldwide, about 8.6 million new TB cases in 2012 were
reported and 1.3 million die every year as a result of TB
(WHO, 2013). Global control of TB has been making vulnerable
by two major threats: Multi-drug resistant tuberculosis (MDRTB) and HIV/AIDS.
According to WHO documents, MDR-TB is a
particularly complicated form of TB characterized by
resistance to at least isoniazid (INH) and rifampicin
(RMP), the two most potent TB drugs. These drugs are
used to treat all persons with TB disease (WHO 2008;
WHO, 2012). On the other hand, since these two drugs
are the two most important first-line TB drugs, their
removal through resistance from the anti-TB drug
armamentarium has serious implications. Moreover in
earlier report indicated that at any given time, about 630
000 people in the world are thought to carry strains of M.
tuberculosis showing resistance to these two drugs that
are currently the most effective against TB (Dye, 2006).
In addition, extensively drug resistant TB (XDR-TB) is a
rare type of MDR-TB that is resistant to isoniazid and
rifampin, plus any fluoroquinolone and at least one of
three injectable second-line drugs (i.e., amikacin,
kanamycin, or capreomycin (Biadglegne et al., 2014).
Since XDR-TB is resistant to first-line and second-line
drugs, patients are left with treatment options that are
more toxic, more expensive, and much less effective (TB
Alliance, 2012a).
According to a recent WHO document, while MDR- TB
is often curable, treatment is complex, requiring expert
management and frequent monitoring. In comparison
with drug-susceptible TB, which takes about 6 to 9
months to treat, recommended treatment for MDR- TB
lasts 18 to 24 months or longer (WHO, 2013).
Furthermore MDR-TB also requires the use of secondline medicines that are not as effective as the first-line
medicines commonly prescribed to treat TB (CDC, 2014;
Nishi et al., 2014). The second-line medicines may also
produce side effects that are difficult to tolerate. To this
view, as study indicated drug resistant strains of
Mycobacterium tuberculosis is of great concern, because
it requires the use of second-line drugs that are difficult to
procure and are much more toxic and expensive than the
first-line regimen (Espinal et al., 2001). Thus, close
monitoring of patients while taking these drugs is critical,
because the medications can also lead to other serious
health problems, such as damage to the kidneys, liver, or heart;
loss of vision or hearing; and changes in behavior or mood
including depression or psychosis (Marks et al., 2014).
cases).Among all incident TB cases globally, 3.6% are
estimated to have MDR-TB. Almost 50% of MDR-TB
cases globally are predictable to occur in China and
India. In addition, in 2008, MDR-TB caused an estimated
150 000 deaths (WHO, 2010). According to WHO (2008),
the increase in prevalence and incidence of MDR- TB are
caused by concurrent factors such as inadequate
treatment regimens, poor case holding, suboptimal drug
quality and transmission of resistant strains (WHO 2008).
Furthermore, one can speculate about the reasons that
retreatment failure rates may be associated with higher
rates of MDR- TB. The relationship may simply be an
association without causation, i.e., that retreatment fails
because a given patient may already have MDR- TB. In
that sense, retreatment failure is simply a marker for
preexisting MDR- TB. However, it is also possible that
retreatment may be a cause of MDR- TB (WHO, 2014a).
The existing WHO recommendations for retreatment
regimens could lead to development of MDR- TB or XDRTB in many instances because suggested retreatment
regimens potentially amount to addition of a drug to a
failing regimen, thereby intensifying the level of drug
resistance (Yanis et al., 2008). Besides, WHO (2011)
indicated that countries conduct surveillance of anti-TB
drug resistance as component of any TB control
programme with four main objectives: (i) measure the
burden of drug-resistant TB and accurately plan
treatment programmes with second-line drugs; (ii) assess
epidemiological trends as a reflection of the effectiveness
of implemented drug-resistant TB prevention and control
activities; (iii) design effective empirical, standardized
regimens for the treatment of TB, particularly for patients
who have already been treated for TB and return with the
disease; and (iv) promptly identify local outbreaks of
drug-resistant TB in order to respond in a timely way
(WHO 2011).Worldwide, the proportion of new cases with
MDR-TB was 3.5% in 2013 and has not changed
compared with recent years. However, much higher
levels of resistance and poor treatment outcomes are of
major concern in some parts of the world (WHO, 2014a).
Obviously, as reports revealed MDR-TB has emerged
as a significant global health concern (Surendra et al.,
2011). To this view, there are upsetting reports of
increasing drug resistance from various parts of the world
which potentially threaten to disrupt the gains achieved in
TB control over the last decade. As a result, drug
resistance has reached alarming levels with the
emergence of strains that are virtually untreatable with
existing drugs.
Evidently,
MDR-TB is essentially man-made
phenomenon largely due to human error in any of
management of drug supply, patient management,
prescription
of
chemotherapy
and
poor
patient
The Prevalence of MDR-TB and its Magnitude
adherence i.e. patients may feel better and halt
their medication, mal-absorption (FMOH, 2011). In fact,
In 2008, an estimated 390 000–510 000 cases of MDRTB emerged globally (best estimate, 440 000
it could be said that the occurrence of MDR-TB itself is an
evidence of systematic failure of the community to tackle
Girma 119
Table: TB cases by incidence, prevalence and mortality by region, 2013 (Source: adapted from The U.S. Government and Global Tuberculosis, 2015).
Incidence
Prevalence
Mortality
Number
(in thousands)
%
(per
Rate
100,000
population)
Number
(in thousands)
(per
Rate
100,000
population)
Number
(in thousands)
(per
Rate
100,000
population)
Region
Africa
Americas
E. Mediterranean
2,600
280
750
29%
3%
8%
280
29
121
2,800
370
1,000
300
38
165
390
14
140
42.0
1.5
23.0
Europe
360
4%
39
460
51
38
4.1
South-East Asia
3,400
38%
183
4,500
244
440
23.0
Western Pacific
Global Total
1,600
9,000
18%
100%
87
126
2,300
11,000
121
159
110
1,100
5.8
16.0
a curable diseases (Singh et al., 2007). Previous
treatment, age group between 25-44 year and less than
65 years, TB/HIV co-infection, poor living conditions,
poverty and malnutrition, homelessness, alcohol abuse,
prisons and overcrowding are the risk factors for MDR-TB
(Kliiman, 2009). For instance in South Africa which is the
world’s third highest burden TB country, only lagging
behind countries with significantly larger populations, such as
China and India, the numbers of MDR-TB patients have
increased due to the concurrent HIV epidemic and inadequate
management of TB (WHO, 2014a).
So far, the magnitude of the problem posed by MDRTB has been estimated in about two thirds of all countries
worldwide through disease surveillance and surveys
(WHO, 2009). According to Alistair et al. (2010), each year new
hot spots of MDR-TB are documented. Among others the
countries that have been most MDR-TB prevalence reported
are include Ethiopia, Indonesia, Nigeria, the Philippines, and
Sudan, Cambodia, Zambia, Bangladesh, China,
Democratic Republic of Congo, Egypt, India, Mexico,
Russia, South Africa, and Ukraine (Alistair et al., 2010).
For instance, in Ethiopia, by 2008, WHO estimated the
incidence MDR-TB among new TB cases to be 1.6 %
(160 cases) and 11.8 % (5000 cases) among previously
treated TB cases (WHO 2010). Additionally, MDR-TB
was found in 32.3% and 75.6% of the new and previously
treated patients, respectively, and 11.9 % of the 612
patients found to have MDR-TB had XDR-TB. Likewise, MDRTB is very common among TB patients throughout Belarus
(Alena et al., 2013).
Globally, in 2013, there were an estimated 480,000
new cases of MDR-TB, and WHO estimates that 9% of
these cases were XDR-TB. MDR-TB has been reported
in most countries, with 27 countries identified as having a high
burden of MDR-TB specifically. XDR-TB has been reported in
100 countries and territories (as shown in the Table) (WHO,
2014a).
The Global Burden of MDR -TB
The emergence of MDR-TB has become a major global
health concern to many countries, especially those in low
and middle-income settings. Among all cases of TB
globally, WHO estimates that nearly 4% of new cases
and 20% of retreatment cases are multidrug-resistant
(WHO, 2014a).
A global estimate of MDR-TB prevalence was included
in the 2011 and 2012 global TB reports, with a best
estimate of 630 000 cases in 2011 (WHO,
2014a).Updated global estimates of MDR-TB incidence
and mortality (best estimates of 450 000 incident cases
and 150 000 deaths in 2012) were presented in the 2013
global TB report. Recently, WHO estimates more than 2
million people will develop MDR-TB between 2011 and
2015 (WHO, 2014a). Furthermore, MDR-TB in 2012,
which is 5% of the 31004 patients for whom there were
drug susceptibility test results (CDC, 2014; Nishi et al.,
2014; WHO, 2014a). Although the Millennium
Development Goal (MDG) to halt and reverse the TB
epidemic by 2015 has been achieved, the global burden
of TB remains enormous with 8.7 million new cases
recorded in 2011 (WHO, 2012).
Ibrahim et al. (2013) noted that the frequency of MDRTB varies greatly between countries. Furthermore, WHO
estimates roughly 630 000 cases of MDR-TB worldwide,
with great variation in the frequency of MDR-TB between
countries (WHO, 2014b). Collected data confirm that
Eastern European and central Asian countries continue
to be the regions with the highest levels of MDR-TB, with
MDR-TB accounting for nearly one third of new TB cases
and two thirds of previously treated TB cases in some
settings (WHO, 2012). There were an estimated 450 000
new MDR-TB cases in 2012, about half of which were in
India, China and the Russian Federation.
According to analyzed data by Dennis et al. (2013)
which reported to WHO by 30 countries, expected to
have more than 1000 MDR-TB cases among notified
patients with pulmonary tuberculosis in 2011.
Accordingly, in the 30 countries, 18% of the estimated
MDR-TB cases were enrolled on treatment in 2011.
Belarus, Brazil, Kazakhstan, Peru, South Africa, and
Ukraine each detected and enrolled on treatment more
Glob. J. Microbiol. Res. 120
than 50% of their estimated cases of MDR-TB. In
Ethiopia, India, Indonesia, the Philippines, and Russia,
enrolments increased steadily between 2009 and 2011
with a mean yearly change greater than 50%: however, in
these countries enrolment in 2011 was low, ranging from
4% to 43% of the estimated cases. In the remaining
countries (Afghanistan, Angola, Azerbaijan, Bangladesh,
China, Democratic Republic of the Congo, Kenya,
Kyrgyzstan, Moldova, Mozambique, Burma, Nepal,
Nigeria, North Korea, Pakistan, South Korea, Thailand,
Uzbekistan, and Vietnam) progress in detection and
enrolment was slower. In 23 countries, a median of 53%
patients with MDR-TB successfully completed their
treatment after starting it in 2008 to 2009.
Moreover, today, together with the burden of infection
due to Human Immunodeficiency Virus (HIV), this coinfection drives most of the TB morbidity and mortality in
many areas like Africa and makes more complicated its
control and decrease in many terms (TB Alliance, 2012b).
Besides, Diana and Alfonso (2013) recently showed that
TB is a human danger and still a significant public health
problem in the world, but particularly in developing
nations. For instance, patients in India, China, the
Russian Federation and South Africa account for nearly
60% of the world are MDR-TB (WHO, 2012).
Convergence of the Epidemics of MDR-TB and HIV
Infection
At no time in recent history has TB become of great
concern as today. Despite highly effective drugs, disease
and deaths due to Mycobacterium tuberculosis are
increasing globally fuelled by the HIV epidemic (WHO,
2014a).
Study
revealed
that
the
human
immunodeficiency virus (HIV) is a driving force behind the
global burden of TB and the development of drugresistant TB (Isaakidis et al., 2012). Besides, HIV
infection has been globally recognized as an important
risk factor for increased susceptibility to TB infection and
the risk of developing active TB (Isaakidis et al., 2013).
Similarly, TB is one of the major causes of death
amongst people with HIV globally (Isaakidis et al., 2012;
WHO, 2013). Furthermore, HIV positive cases are also
more likely to have extra-pulmonary disease than nonHIV infected cases. HIV co-infection is a significant
challenge for the prevention, diagnosis, and treatment of
MDR and XDR-TB (Neel et al., 2010). HIV is a powerful
risk factor for development of all forms of TB including
DR-TB and for this reason, DR-TB is often associated
with higher mortality rates in HIV infected when
compared with the non-infected (Mrinalini et al., 2014).
The synergy between TB and HIV is strong i.e., in high
HIV prevalence population, TB is a leading cause of
morbidity and mortality, and HIV is driving the TB
epidemic in many countries, especially in sub-Saharan
Africa (CDC, 2013).Consequently, the spread of TB and
HIV is aggravated by socio-economic factors such as
poverty and low levels of literacy (WHO, 2007).
Moreover, MDR-TB patient co-infected with HIV is
subject to long and potentially toxic treatment that may
make the patient debilitated stressed, and de-motivated
(Isaakidis et al., 2012). Additionally, dependence on the
family for support, discrimination, and/or financial
problems can further influence the mental wellbeing of
patients (Mrinalini et al., 2014). Consequently,
management of MDR-TB patients co-infected with HIV is
highly challenging. With growing evidence showing
psychiatric illnesses such as depression, anxiety and
psychosis to be associated with MDR-TB and HIV
mental health care for patients with these two
stigmatizing and debilitating diseases demands attention
(Vega et al., 2004; Ownby et al., 2010; Isaakidis et al.,
2012; Mrinalini et al., 2014).
According to WHO (2013), recent global data have
shown rising rates of drug-resistant TB in sub-Saharan
Africa, the region also suffering from the world’s highest
burden of HIV/AIDS. Kiliman (2009) noted that, the
percentage of MDR-TB among HIV infected individuals
was found to be three times higher. Among 136
suspected cases of MDR-TB, HIV-infection was
confirmed among 114 (88%) in South Africa (Scott et al.,
2010). Likewise, Federal Ministry of Health of Ethiopia
(FMOH, 2007) has documented that the human
immunodeficiency virus (HIV) pandemic presents a
massive challenge to the control of TB at all levels.
Generally, as implication of HIV infection and MDR-TB
convergence, given the severe consequences of HIV
infection and MDR-TB occurring together, as well as the
geographic
overlap
in
many
settings,
major
consequences for HIV treatment and care and for
addressing MDR-TB control can be anticipated (Wells et
al., 2007).
Global Burden of Tuberculosis and HIV Co-infection
TB and HIV act in deadly synergy (WHO, 2007). HIV
infection increases the risk of TB infection on exposure,
progression from latent infection to active TB, risk of
death if not timely treated for both TB and HIV and risk of
recurrence even if successfully treated. Correspondingly,
TB is the most common opportunistic infection and cause
of mortality among people living with HIV, difficult to
diagnose and treat owing to challenges related to comorbidity, pill burden, co-toxicity and drug interactions
(Isaakidis et al., 2011; WHO, 2012).
Worldwide about 11.1 million adults are co-infected
with TB and HIV (FMOH, 2007). For instance, 70% of coinfected people are living in sub-Saharan Africa 20% in
South East Asia and 4% in Latin America and the
Caribbean,
respectively. On the other hand,
approximately half a million people worldwide were
diagnosed with MDR-TB in 2006; more than 50 countries
by the end of last year, including the United States, had
reported XDR-TB (WHO, 2007; CDC, 2013). Likewise, in
Girma 121
Ethiopia routine data from 44 sites in the year 2005/6
showed 41% of TB patients are HIV positive. Another
routine data collected in 2006/7 showed that the coinfection is 31% (FMOH, 2011). Recently, WHO (2014a)
documented that in 2013, 1.5 million people died from
TB, including 360 000 among people who were HIVpositive with 1.1 million cases among people living with
HIV.
it may be confounded by previous treatment. To this
view, a French study stratifying results by country of birth
found a higher risk of MDR-TB in both new and
previously treated patients from sub-Saharan Africa,
while patients from North Africa were at higher risk of
MDR-TB only after a previous treatment (Schwoebel et
al., 1998).
Role of HIV
Risk Factors for MDR-TB
According to Espinal et al. (2001) and Caminero (2005),
the global increase in drug resistance, particularly MDRTB, reflects, at least in part, inappropriate use of anti-TB
drugs during the treatment course of TB patients with
drug susceptible strains. Additionally, investigations have
broadly described that the risk factors of TB may be
biomedical (such as HIV infection, diabetes, tobacco,
malnutrition, silicosis, malignancy), environmental (indoor
air pollution, ventilation) or socioeconomic (crowding,
urbanization, migration, poverty) factors have been
shown to be associated with the increased prevalence of
MDR-TB (Faustini et al., 2006; Gulam, 2012).
Effect of Treatment and Failure of Retreatment in
Chronic TB Patients
Previous treatment has been widely recognized as
inducing multidrug resistance of Mycobacterium
tuberculosis and the prevalence of MDR-TB has been
estimated to be up to 10 times higher after unsuccessful
treatment (Pablo-Me´ndez et al., 1998). On the other
hand, Chronic TB patients are defined as patients who
are sputum positive at the end of the intensive phase and
on completion of re-treatment regimen. These patients
have the highest MDR-TB rates, often greater than 80%
(WHO, 2008). Furthermore, for the relapse and default,
erratic drug intake or early relapse may point to possible
MDR-TB. Relapses within the first six months post
treatment may have similar MDR-TB rates as failures.
Repeated interruption of treatment can also result in
selection for resistant mutants. Exposure to a confirmed
MDR-TB patient is also another important issue (CDC,
2012). Accordingly, most studies have shown that close
contacts of MDR-TB patients have very high rates of
MDR-TB. This includes children, who should be started
on MDR-TB therapy empirically until proven not to have
MDR-TB (WHO, 2008).
Influence of Immigration
Immigration has been suggested as one factor leading to
the increased prevalence of MDR-TB in European
countries (Espinal et al., 2001; CDC, 2012). The
association between MDR-TB and being foreign born
could be due to a higher risk of transmission of MDR
strains of Mycobacterium tuberculosis for immigrants, but
Numerous MDR-TB outbreaks have been documented in
HIV positive individuals as a result of the depressed
immune system and high susceptibility to infection (WHO,
2008). Initially it seemed that HIV status was a risk factor
for MDR-TB, but nosocomial outbreaks largely accounted
for the association and, currently, the prevalent
hypothesis is that HIV infection favours the transmission
of multidrug resistant strains of M. tuberculosis (McCray
and Onorato, 2000). WHO documented that medical risk
factors include co-infection with HIV; people with HIV are
21 to 34 times more likely to develop TB, and accounted
for about 13% of all TB cases globally in 2010.
Development of the disease is also linked to certain
social risk factors, notably drug or alcohol abuse, poor
housing conditions, homelessness and imprisonment
(WHO, 2010).
Previous history of tuberculosis treatment
Several studies reported that previous history of antituberculosis treatment is the most widely reported risk
factor for MDR-TB. Previously treated TB has strongest
association with MDR-TB in addition to the duration of
previous TB treatment Patients who received previous
anti-tuberculosis treatment had a 4-fold increased odds of
multidrug resistance(Kiliman, 2009; Kai and Altraja,
2009; Alistair et al., 2010).
Age and MDR-TB
Reports indicated that younger age is known to be the
significant contributor for development of MDR-TB
(Fairlie, 2011; ECDC; 2012). Contrary to this, the study
conducted in South Africa showed that age was not a
significant risk factor, it was found that MDR-TB was
cultured from the blood in patients as young as 8 years
and as old as 62 years (Scott et al., 2010). Moreover, as
WHO (2010) report indicated in a surveillance data
collected from 13 countries of Central and Eastern
Europe, the frequency of MDR-TB was much higher in all
age groups compared with the rest of the countries (all
high-income) and peaked in young adulthood (WHO
2010). On the other hand, WHO report noted that TB
affects more men than women, and mostly adults in their
productive years (WHO, 2012). However, all age groups
are at risk but more than 95% of cases occur in
developing countries. Furthermore, there was a clear
Glob. J. Microbiol. Res. 122
association observed between MDR-TB and age under
65 years, but the association was weak and more
heterogeneous for ages under (Espinal et al., 2001;
Fairlie, 2011). This can reflect the year in which effective
anti-tuberculosis drugs such as rifampicin were
introduced (Pablo-Me´ndez et al., 1998).
Sex and MDR-TB
According to WHO (2010) drug resistance surveillance
report, among 38 countries and 3 territories the odds ratio
of harbouring MDR-TB strains for female TB cases
compared with male TB cases was 1.1, showing no
overall association between MDR-TB and sex of the
patient. In South Africa, although a higher number of
male than female MDR-TB cases were reported (4826
and 4615 cases, respectively), data from a total of 81,794
TB patients with known sex (95% of all patients) indicates
that female TB cases have a 1.2 times higher odds of
harbouring MDR-TB strains than male TB cases. Data
from Australia, the Netherlands and the United States of
America also show a higher risk of MDR-TB in female
patients (WHO 2010). On the other hand, MDR-TB
patients were more likely to be male in Western Europe,
where previous treatment was the most important
determinant of MDR-TB. In Eastern Europe, where the
risk of transmission is greater, male sex was not a risk
factor for MDR-TB. Hence, it could be hypothesized that
women are more compliant with treatment and therefore
less likely to receive inadequate treatment (CDC, 2012).
In a study conducted in Peru among 673 patients, more
than half of diagnosed and confirmed (60.8%) MDR-TB
was male which shows that gender is a risk factor for the
development of MDR-TB (Molly et al., 2008).
Furthermore, in a systematic review conducted by
Faustini et al. (2006), there was a stronger association of
being a male sex as a risk factor for MDR-TB in the eight
studies carried out in Western Europe and heterogeneity
between studies were very low. Men were at lower risk of
MDR-TB in the three studies carried out in the former
USSR with a high heterogeneity between studies.
Moreover, People living with HIV have a higher risk of
MDR-TB (Wells et al., 2007; Dubrovina et al., 2008;
WHO, 2008). Generally, people living with HIV are
particularly vulnerable to the impact of drug resistant TB
due to the difficulties and delays in the diagnosis (Wells
et al., 2007), complications of concomitant treatment with
TB and antiretroviral therapy (ART) (Havlir et al., 2008)
and poor TB infection control measures in many HIV care
settings (Gandhi et al., 2006; Kawai et al., 2006; ECDC,
2013).
Poor TB Treatment Adherence
Adherence to treatment means that a patient is following
the recommended course of treatment by taking all the
prescribed medications for the entire length of time
necessary. On the other hand, adherence can influence
the emergence of new disease strains, individual health
outcomes, and the overall cost of health care (Comstock,
1999). For example, MDR-TB emerged largely because
of widespread no adherence to treatment for TB disease.
Poor adherence to treatment remains a major obstacle to
efficient TB control in developing countries. Innovative
strategies to improve access and adherence to treatment
are needed. Poor adherence were related to age
differences as younger patients are often occupied by
study, work or other activities on a daily basis, in contrast
with the more sedentary lifestyle post-retirement age
(Law et al. 2008).
Site of TB Involvement
The clinical manifestations of TB are of two types:
Pulmonary and Extra-pulmonary forms of TB (EPTB), the
former being the commonest (Robert, 2013). Pulmonary
TB features (Cough, fever, sweats, weight loss and
haemoptysis) and extra-pulmonary lymphnode swelling
(lymphadenitis) are leads that used in identifying
diseases symptomatically (Gizachew et al., 2013). In
EPTB highly vascular areas such as lymph nodes,
meninges, kidney, spine and growing ends of the bones
are commonly affected. The other sites are pleura,
pericardium, peritoneum, liver, gastro-intestinal tract,
genito-urinary tract and skin. Before the advent of the HIV
epidemic, approximately 85% of reported tuberculosis
cases were pulmonary only, with the remaining 15%
being extra-pulmonary or both pulmonary and extrapulmonary sites (Farer et al., 1979).
In a study conducted elsewhere by Law et al. (2008)
noted that, the vast majority of MDR-TB cases suffered
from pulmonary TB (98%), and only 2% presented with
extra pulmonary TB alone. On the contrary, a study
conducted in South Africa indicated that about one
quarter of drug resistant TB patients were diagnosed with
extra-pulmonary TB in addition to pulmonary TB
(Andrews et al., 2010). Another study conducted in
Tomsk, Russian Federation, revealed that sputum-smear
positivity was significantly associated with MDR-TB
(Gelmanova et al., 2007).
Causes of drug-resistant tuberculosis
Drug-resistant TB has microbial, clinical, and
programmatic
causes.
From
a
microbiological
perspective, the resistance is caused by a genetic
mutation that makes a drug ineffective against the mutant
bacilli (Joshi and Jajoo, 2010). Besides, an inadequate or
poorly administered treatment regimen allows drugresistant mutants to become the dominant strain in a
patient infected with TB (Joshi and Jajoo, 2010).
However it should be stressed that MDR-TB is a manmade phenomenon such as poor treatment, poor drugs
and poor adherence lead to the development of MDR-TB.
Girma 123
Resistance to isoniazid and rifampicin drugs was
reported in earlier reports (Zhang et al., 1992; Telenti et
al., 1993; Piatek et al., 2000). Accordingly, resistance to
isoniazid is due to mutations at one of two main sites, in
either the katG or inhA genes while resistance to
rifampicin is nearly always due to point mutations in
the rpo gene in the beta subunit of DNA-dependent RNA
polymerase. These mutations are not directly connected,
and so separate mutations are required for organisms to
change from a drug-susceptible isolate to MDR-TB.
In addition, CDC (2012) report indicated that resistance
to anti-TB drugs can occur when isoniazid and rifampicin
drugs are misused or mismanaged. Examples include
when patients do not complete their full course of
treatment; when healthcare providers prescribe the
wrong treatment, the wrong dose, or length of time for
taking the drugs; when the supply of drugs is not always
available; or when the drugs are of poor quality (CDC,
2012). Biologically however, drug resistance develops in
bacteria because of naturally-occurring changes in their
genes. When bacteria are treated with a drug, these
changes allow some to survive. Continued exposure to
the drug kills any remaining drug-susceptible bacteria,
providing the ideal environment for the resistant forms to
flourish. Eventually that strain of bacteria can become
completely resistant to the drug in question. Bacteria may
develop resistance to more than one drug (WHO, 2012).
Prevention of MDR-TB
The emergence of resistance to drugs used to treat TB,
and particularly MDR-TB, has become a significant public
health problem in a number of countries and an obstacle
to effective TB control (Central TB Division, 2006; Saira
Zai et al., 2010). Investigation noted that poor treatment
practices breed drug resistance. Areas with a poor TB
control tend to have higher rates of drug resistant TB. On
the other hand, it has been acknowledged that good
treatment is a pre-requisite to the prevention of
emergence of resistance (Keshavjee and Farmer, 2010).
Furthermore, the most important thing a person can do to
prevent the spread of MDR- TB is to take all of their
medications exactly as prescribed by their health care
provider (WHO, 2013). No doses should be missed and
treatment should not be stopped early (Jain and Dixit,
2008). Patients should tell their health care provider if
they are having trouble taking the medications. If patients
plan to travel, they should talk to their health care
providers and make sure they have enough medicine to
last while away (ECDC, 2014; WHO, 2014a).
Additionally, all patients with DR-TB must be offered HIV
counseling and testing, and those who are co- infected
must be started on cotrimoxazole and antiretroviral
treatment (ART) as soon as ARV adherence counseling
is completed. All co-infected MDR/XDR-TB/HIV patients
qualify to receive antiretroviral therapy (ART) regardless
of their CD4 count (WHO, 2013). Earlier reports by
Paramsivan (2003) and Davies (2003) noted that the key
to the successful prevention of the emergence of drug
resistance is adequate case finding, prompt and correct
diagnosis, and effective treatment of infected patients.
This can be achieved through the use of Directly
Observed Therapy Short-course (DOTS).
Generally, prevention of emergence of MDR-TB in the
community is more imperative rather than its treatment. It
is impossible to tackle the problem of drug-resistant TB
through treatment alone; each MDR-TB case costs more
than 20 times the cost of a simple drug-susceptible TB
case. Therefore basic TB diagnostic and treatment
services would be prioritized with the view that DOTS
reduces the emergence of MDR-TB, and therefore the
need for Programmatic Management of Drug-Resistant
TB (PMDT) over time (Udwadia, 2001; Saira Zai et al.,
2010).
CONCLUSION
In this review, it is noted that Tuberculosis (TB) remains a
major global health problem. Globally, TB is the second
largest cause of death from an infectious agent after
HIV/AIDS and in developing countries in particular.
Antibiotic resistance is a growing impediment to the
control of infectious diseases worldwide, TB being among
them. Multidrug-resistant tuberculosis (MDR-TB) caused
by Mycobacterium tuberculosis resistant to both isoniazid
(INH) and rifampicin (RMP) with or without resistance to
other drugs is among the most worrisome elements of the
pandemic of antibiotic resistance. Several reports
indicated that previous exposure of anti-TB treatment
increased the risk of MDR-TB worldwide besides other
risk factors. Moreover, the convergence of MDR-TB and
HIV has created a new and dangerous major epidemic
and the epidemic of MDR-TB and HIV co-infection has
been a wake-up call to the public health community
globally. Therefore, strengthening rapid diagnostic
assays to detect highly drug-resistant TB are essential in
preventing delays in treatment of MDR-TB and limiting its
spread. Moreover, development of new drugs to
effectively treat both MDR-TB and XDR-TB in shorter
period of time is urgently needed.
REFERENCES
Alena S, Henadz H, Aksana Z, Evgeni S, Andrei A, Sven H, Valiantsin
R,
Andrei
D,
Pierpaolo C, Masoud D, Wayne G and Matteo Z (2013). Multidrugresistant
tuberculosis in Belarus: the size of the problem and associated risk
factors. Bull World Health Organ., 91:36–45.
Alistair D, Calver A, Falmer M, Murray O, Strauss J, Elizabeth M,
Streicher M, Hanekom T, Liversage M, Masibi P, van Helden D,
Robin M and Thomas C (2010). Emergence of Increased Resistance
and Extensively Drug-Resistant Tuberculosis despite Treatment
Adherence, South Africa. Emerging Infectious Diseases, 16: 2010.
Glob. J. Microbiol. Res. 124
Biadglegne F, Ulrich S and Arne C (2014). Multidrug-resistant
tuberculosis in Ethiopia: efforts to expand diagnostic services,
treatment and care. Antimicrobial Resistance
and Infection
Control, 3:31.
Caminero JA (2005).Management of multidrug-resistant tuberculosis
and patients in retreatment. Eur Respir J., 25: 928- 936.
CDC (2013). Reported Tuberculosis in the United States, Atlanta, GA:
U.S. Department of Health and Human Services, CDC. Available at
www.cdc.gov/tb
CDC (2014). European Centre for Disease Prevention and
Control/WHO Regional Office for Europe. Tuberculosis surveillance
and monitoring in Europe. Stockholm: European Centre for Disease
Prevention and Control.
CDC (2012). TB Elimination Multidrug-Resistant Tuberculosis (MDR
TB).
Charles D, Wells J, Peter C, Cegielski L, Nelson J, Kayla F, Laserson F,
Timothy H, Alyssa F, Kenneth G and Karin W (2007). HIV Infection
and Multidrug-Resistant Tuberculosis-The Perfect Storm. The Journal
of Infectious Diseases, 86-107.
Dara M, Grezemaska M, Kimerling M, Reyes M and Zagoriskiy A
(2009). Gridlines for control of Tuberculosis in prisons.
http://pdf.usaid.gov/pdf_docs/PNADP462.pdf.
Diana MC. and Alfonso JR (2013). Epidemiological Burden of
Tuberculosis in Developing Countries. Current Topics in Public
Health, 318-340.
Dubrovina, I, Miskinis K and Gilks C (2008). Drug-resistant tuberculosis and HIV
in Ukraine: a threatening convergence of two epidemics? International Journal
of Tuberculosis and Lung Disease 12, 756–762.
Dye, C. (2006). Global epidemiology of tuberculosis. Lancet; 367: 938-940.
ECDC (2012). European Centre for Disease Prevention and Control:
Management of contacts of MDR TB and XDR TB patients.
ECDC (2013). European Centre for Disease Prevention and
Control/WHO Regional Office for Europe. Tuberculosis surveillance
and monitoring in Europe 2013. Stockholm: The Centre; 2013.
ECDC (2014). TECHNICAL REPORT. Healthcare system factors
influencing treatment results of MDR TB patients.
Espinal MA, Laszlo A, Simonsen L, Boulahbal F, Kim SJ, Reniero A,
Hoffner S, Rieder HL, Binkin N, Dye C, Williams R and Raviglione
MC (2001). Global Trends in Resistance to Antituberculosis Drugs. N
Engl J Med., 344: 1294-1303.
Fairlie E (2011). High prevalence of childhood multi-drug resistant
tuberculosis in Johannesburg, South Africa: a cross sectional study.
BMC Infectious Diseases, 11:28.
Faustini A, Hall AJ and Perucci CA (2006). Risk factors for multidrug
resistant tuberculosis in Europe: a systematic review. Thorax, 61:
158-163.
FHAPCO/FMOH (2007). Single Point HIV Prevalence Estimate.
FMOH (2007). Implementation Guideline for TB/HIV Collaborative
Activities in Ethiopia.
FMOH (2011). Tuberculosis Prevention and Control Program; special
issue for world TB day Addis Ababa: Government publisher.
Pablo-Me´ndez A, Raviglione MC and Laszlo A (1998).
Global
surveillance for antituberculosis-drug resistance, 1994–1997. N Engl
J Med., 338:1641–1649.
Piatek A, Telenti A and Murray M (2000). Genetotypic analysis of
Mycobacterium tuberculosis in two distinct populations using
molecular
beacons:
implications
for
rapid
susceptibility
testing. Antimicob Agents Chemother., 44:103–10.
Raviglione M, Marais B and Floyd K (2012). Scaling up interventions to
achieve global tuberculosis control: progress and new developments.
Lancet, 379: 1902–13.
Schwoebel V, Decludt B and de Benoist AC (1998). Multidrug resistant
tuberculosis in France 1992–1994: two case-control studies. BMJ,
317:630–631.
Scott K, Heysell T, Thomas A, Neel R, Gandhi A, Moll P, François J,
Eksteen Y, Coovadia L, Roux P, Babaria U, Lalloo G, Friedland S
TB Alliance (2012b).
The TB Pandemic. Available at
http://www.tballiance.org/why/the-tb-pandemic.php.
Telenti A, Imboden P and Marchesi F (1993). Detection of rifampicin
resistance
mutations
in Mycobacterium
tuberculosis.
Lancet, 341, 647–50.
Vega P, Sweetland A, Acha J, Castillo H, Guerra D, Smith F
(2004). Psychiatric issues in the management of patients with
Gulam NA (2012). Revised National TB Control Programme Annual
Status Report. TB India, Nirman Bhawan, New Delhi - 110 108.
Havlir DV, Getahun H, Sanne I and Nunn P (2008). Opportunities and
challenges for HIV care in overlapping HIV and TB epidemics. JAMA,
300: 423–430.
Isaakidis, P., Cox, H.S., Varghese, B., Montaldo, C., Da, S., Mansoor,
H. (2011). Ambulatory multi-drug resistant tuberculosis treatment
outcomes in a cohort of HIV-infected patients in a slum setting in
Mumbai, India. PLoS One 2011.
Isaakidis P, Rangan S, Pradhan A, Ladomirska J, Reid T and Keilman K
(2013). ‘I cry every day’: experiences of patients co-infected with HIV
and multidrug-resistant tuberculosis. Trop Med Int Health, 18: 11281133.
Isaakidis P, Varghese B, Mansoor H, Cox H, Ladomirska J and
Saranchuk P (2012). Adverse events among HIV/MDR-TB coinfected
patients receiving antiretroviral and second line anti-TB treatment in
Mumbai, India. PLoS One 2012; 7: e40781.
Kai K and Alan A (2009). Predictors of Extensively Drug-Resistant
Pulmonary Tuberculosis. Ann Intern Med., 150:766-775.
Kawai V, Soto G and Gilman RH (2006). Tuberculosis mortality, drug
resistance, and infectiousness in patients with and without HIV
infection in Peru. American Journal of Tropical Medicine and
Hygiene, 75: 1027–1033.
Kliiman K (2009). Highly drug resistant tuberculosis in Estonia: Risk
factors and predictors of poor treatment outcome. Estonia: Tartu
University press.
Marks S (2014). Treatment Practices, Outcomes, and Costs of
Multidrug Resistant and Extensively Drug Resistant Tuberculosis in
the United States. Emerg Infect Dis.
McCray McCray E and Onorato IM (2000). The interaction of human
immunodeficiency virus and multidrug-resistant Mycobacterium
tuberculosis. In:Bastian, I. and Portaels, F. Multidrug-resistant
tuberculosis. Netherlands: Kluwer Academic Publishers, 45–57.
Mrinalini D, Petros I, Rafael V, Ajay M, Sharath B, Asmaa V, Santosh
J, Bindoo J and Joanna L (2014). HIV, multidrug-resistant TB and
depressive symptoms: when three conditions collide. Glob Health
Action 2014.
Neel R, Gandhi N, Sarita S, Jason R, Andrews V, Vella A, Moll M,
Scott D, Weissman C, Marra U, Lalloo G and Gerald H (2010). HIV
Co-infection in Multidrug- and Extensively Drug-Resistant
Tuberculosis Results in High Early Mortality. Am J Respir Crit Care
Med., 181: 80–86.
Nishi A, Bedi S, Rajpal B, Harinath R, Jain K and Rai S (2014). Indian J
Tuberc. 61: 95-97.
Olatunji, B.O., Mimiaga, M.J., O’Cleirigh, C., Safren, S.A. (2006). A
review of treatment
Ownby R, Jacobs R, Waldrop-Valverde D and Gould F (2010).
Depression care and prevalence in HIV-positive individuals.
Neurobehav HIV Med., 2: 73-83.
and Shah S (2010). Blood cultures for the diagnosis of multidrug
resistant and extensively drug-resistant tuberculosis among HIVinfected patients from rural South Africa: a cross-sectional study.BMC
Infectious Diseases, 10:344.
Singh J, Upshur R and Padayatchi N (2007). XDR-TB in South Africa:
No time for denial or complacency. PLoS Med 4(1): e50.
oi:10.1371/journal.pmed.0040050.
Sohail M (2006). Tuberculosis: A re-emerging enemy. Journal of
Molecular and Genetic Medicine, 2: 87-88.
Surendra K, Sharma S, Saha PK, Ninoo G, Arora S, Gupta D, Urvashi
S, Hanif M and Vashisht R (2011). Prevalence of multidrug-resistant
tuberculosis among Category II pulmonary tuberculosis patients.
Indian J Med Res, 312-315.
TB
Alliance
(2012a).
MDR-TB/XDR-TB.
Available
at
http://www.tballiance.org/why/mdr-xdr.php.
multidrug-resistant tuberculosis. Int J Tuberc Lung Dis., 8:
749 -759.
Wells CD, Cegielski JP and Nelson LJ (2007). HIV infection and
multidrug-resistant tuberculosis: the perfect storm. Journal of
Infectious Diseases 196(Suppl. 1), S86–S107.
WHO (1996). Guidelines for the management of drug-resistant
tuberculosis. Geneva, (WHO/TB/96.210 (Rev. 1)).
Girma 125
WHO (2007). Global Tuberculosis Control.
WHO. (2008).Guidelines for the programmatic management of drugresistant tuberculosis: Emergency Update.
WHO (2009). Global tuberculosis control: surveillance, planning,
financing: A WORLD FREE OF TB. Geneva.
WHO (2010).The global plan to stop TB 2011-2015: Transforming the
fight towards the elimination of tuberculosis. Geneva.
WHO (2011). Partners call for increased commitment to tackle MDRTB.
Available
at
http://www.who.int/mediacentre/news/releases/2011/TBday_2011032
2/en/index.html.
WHO (2012). Global tuberculosis report 2012. Geneva, Switzerland.
WHO (2013). WHO report. Global Tuberculosis control. Geneva:
(http://www.who.int/tb/data).
WHO.(2014).
Global
Tuberculosis
Report.
Available
at:
http://www.who.int/tb/publications/global_report/en.
Yanis B, Bennett N, Angad S, Alyssa S and Neil S (2008).
Underreported Threat of Multidrug-Resistant Tuberculosis in Africa.
Emerging Infectious Diseases, 14: 1345-1352.
Zhang Y, Heym B and Allen B (1992). The catalase-peroxidase gene
and isoniazid resistance in M.tuberculosis. Nature, 358, 591–3.
Zhao Y, Xu S, Wang L (2012). National survey of drug-resistant
tuberculosis in China. N Engl J Med., 366: 2161–2170